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Biotinylation of an...
Biotinylation of an acetylenic tricyclic bis(cyanoenone) lowers its potency as an NRF2 activator while creating a novel activity against BACH1
- Artikel/kapitelEngelska2022
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LIBRIS-ID:oai:gup.ub.gu.se/319488
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https://gup.ub.gu.se/publication/319488URI
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https://doi.org/10.1016/j.freeradbiomed.2022.08.041DOI
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The transcription factor BACH1 regulates the expression of a variety of genes including genes involved in oxidative stress responses, inflammation, cell motility, cancer cell invasion and cancer metabolism. Based on this, BACH1 has become a promising therapeutic target in cancer (as anti-metastatic target) and also in chronic conditions linked to oxidative stress and inflammation, where BACH1 inhibitors share a therapeutic space with activators of transcription factor NRF2. However, while there is a growing number of NRF2 activators, there are only a few described BACH1 inhibitors/degraders. The synthetic acetylenic tricyclic bis(cyanoenone), (+/-)-(4bS,8aR,10aS)-10a-ethynyl-4b,8,8-trimethyl-3,7-dioxo-3.4b,7,8,8a,9,10, 10a-octahydrophenanthrene-2,6-dicarbonitrile, TBE31 is a potent activator of NRF2 without any BACH1 activity. Herein we found that biotinylation of TBE31 greatly reduces its potency as NRF2 activator (50-75-fold less active) while acquiring a novel activity as a BACH1 degrader (100-200-fold more active). We demonstrate that TBE56, the biotinylated TBE31, interacts and promotes the degradation of BACH1 via a mechanism involving the E3 ligase FBXO22. TBE56 is a potent and sustained BACH1 degrader (50-fold more potent than hemin) and accordingly a powerful HMOX1 inducer. TBE56 degrades BACH1 in lung and breast cancer cells, impairing breast cancer cell migration and invasion in a BACH1-dependent manner, while TBE31 has no significant effect. Altogether, our study identifies that the biotinylation of TBE31 provides novel activities with potential therapeutic value, providing a rationale for further characterisation of this and related compounds.
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Biuppslag (personer, institutioner, konferenser, titlar ...)
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Casares, L.
(författare)
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Higgins, M.
(författare)
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Ali, Kevin X.Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för kirurgi,Wallenberg Centre for Molecular and Translational Medicine,Institute of Clinical Sciences, Department of Surgery(Swepub:gu)xalike
(författare)
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Honda, T.
(författare)
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Wiel, Clotilde,1987Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för kirurgi,Wallenberg Centre for Molecular and Translational Medicine,Institute of Clinical Sciences, Department of Surgery(Swepub:gu)xwiecl
(författare)
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Sayin, Volkan I.,1983Gothenburg University,Göteborgs universitet,Wallenberg Centre for Molecular and Translational Medicine,Institutionen för kliniska vetenskaper, Avdelningen för kirurgi,Institute of Clinical Sciences, Department of Surgery(Swepub:gu)xsayvo
(författare)
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Dinkova-Kostova, A. T.
(författare)
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de la Vega, L.
(författare)
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Göteborgs universitetInstitutionen för kliniska vetenskaper, Avdelningen för kirurgi
(creator_code:org_t)
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Ingår i:Free Radical Biology and Medicine: Elsevier BV191, s. 203-2110891-5849
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Moreno, R.
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Casares, L.
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Higgins, M.
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Ali, Kevin X.
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Honda, T.
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Wiel, Clotilde, ...
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Sayin, Volkan I. ...
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Dinkova-Kostova, ...
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de la Vega, L.
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Göteborgs universitet